Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-08-22
2003-04-22
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S221000, C540S473000, C540S556000
Reexamination Certificate
active
06552012
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel heteroaryl diazabicycloalkane derivatives which are found to be cholinergic ligands at the nicotinic acetyl choline receptors.
Due to their pharmacological profile the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the central nervous system (CNS), diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders related to neurodegeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.
BACKGROUND ART
The endogenous cholinergic neurotransmitter, acetylcholine, exert its biological effect via two types of cholinergic receptors, the muscarinic Acetyl Choline Receptors (mAChR) and the nicotinic Acetyl Choline Receptors (nAChR).
As it is well established that muscarinic acetyl choline receptors dominate quantitatively over nicotinic acetyl choline receptors in the brain area important to memory and cognition, and much research aimed at the development of agents for the treatment of memory related disorders have focused on the synthesis of muscarinic acetyl choline receptor modulators.
Recently, however, an interest in the development of nAChR modulators has emerged. Several diseases are associated with degeneration of the cholinergic system i.e. senile dementia of the Alzheimer type, vascular dementia and cognitive impairment due to the organic brain damage disease related directly to alcoholism. Indeed several CNS disorders can be attributed to a cholinergic deficiency, a dopaminergic deficiency, an adrenergic deficiency or a serotonergic deficiency.
SUMMARY OF THE INVENTION
The present invention is devoted to the provision novel nicotinic receptor modulators, which modulators are useful for the treatment of diseases or disorders related to the cholinergic receptors, and in particular the nicotinic acetyl choline receptor (nAChR).
Due to their pharmacological profile the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the central nervous system (CNS), diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders related to neurodegeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.
The compounds of the invention may also be useful as diagnostic tools or monitoring agents in various diagnostic methods, and in particular for in vivo receptor imaging (neuroimaging), and they may be used in labelled or unlabelled form.
In its first aspect the invention provides novel diazabicycloalkane derivatives represented by the general Formula I
any of its enantiomers or any mixture thereof, an N oxide thereof, a pharmaceutically acceptable salt thereof, in a labelled or un-labelled form, wherein,
n is 2 or 3; and
m is 1, 2 or 3; and
one of R and R
1
represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, or aralkyl; and
the other of R and R
1
represents a monocyclic 5 to 6 membered heterocyclic group,
which monocyclic heterocyclic group may be substituted one or more times with alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, hydroxyalkoxy, alkoxycycloalkyl, cycloalkoxy, cycloalkoxyalkoxy,alkenyl, alkenoxy, alkoxyalkenyl, alkynyl, alkynoxy, alkoxyalkynyl, alkylthio, alkenylthio, alkynylthio, alkylseleno, alkenylseleno, alkynylseleno, methylenedioxy, trifluoromethanesulfonyloxy, halogen, —OH, —CF
3
, —OCF
3
, —CN, amino, nitro, oxime, or a group of the formula —COOR
3
, —CONR
2
R
3
, —NH—CO
2
R
2
, —NHCO—R
2
, —OCO—NR
2
R
3
; in which formulae R
2
and R
3
independently of each another represents hydrogen or alkyl; or
which monocyclic heterocyclic group may be substituted with an aryl group, which aryl group is optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy, alkenoxy, alkynoxy, methylenedioxy, halogen, —OH, —CF
3
, —OCF
3
, —CN, amino, nitro, oxime, alkyloxime, or acyloxime; or
which monocyclic heterocyclic group may be substituted with a group of the formula “—X-alkyl-Y-alkyl”, wherein X and Y independently of each another represents O (epoxy), S, NH, N-alkyl or Se, and the alkyl group is optionally substituted with alkoxy, or thioalkoxy; or
which monocyclic heterocyclic group may be substituted with a group of the formula “—X-(ALK)
o
-aryl”, wherein X represents O, S, NH, N-alkyl or Se; “ALK” represents alkyl, alkenyl or alkynyl; o is 0 or 1; and aryl is optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, alkenoxy, alkynoxy, methylenedioxy, halogen, —OH, —CF
3
, —OCF
3
, —CN, amino, nitro oxime, alkyloxime, acyloxime; or
which monocyclic heterocyclic group may be substituted with a group of the formula “—X-(ALK)
o
—Z”, wherein X represents O, S, NH, N-alkyl or Se; “ALK” represents alkyl, alkenyl or alkynyl; o is 0 or 1; and Z represents a 5- or 6-membered monocyclic heterocyclic group, which group is optionally substituted one or more times with alkyl cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy, alkenoxy, alkynoxy, methylenedioxy, halogen, —OH, —CF
3
, —OCF
3
, —CN, amino, nitro, oxime, alkyloxime, or acyloxime; or
which monocyclic heterocyclic group may be substituted with another monocyclic 5 to 6 membered heterocyclic group, which additional heterocyclic group is optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, alkenoxy, alkynoxy, methylenedioxy, halogen, —OH, —CF
3
, —OCF
3
, —CN, amino, nitro, oxime, alkyloxime, or acyloxime; or
which monocyclic heterocyclic group may be substituted with a group of the formula “(ALK)
o
-HET”, wherein “ALK” represents alkyl, alkenyl or alkynyl; o is 0 or 1; and “HET” represents a non-aromatic heterocyclic group; or
the other of R and R
1
represents a bicyclic heterocyclic group, composed of a 5 to 6 membered monocyclic heterocyclic group fused to a benzene ring, and
which bicyclic heterocyclic group may be substituted one or more times with
alkyl; cycloalkyl; cycloalkylalkyl; alkenyl; alkynyl; alkoxy; alkoxy-alkoxy; cycloalkoxy; alkenoxy; alkynoxy; methylenedioxy; halogen; —OH; —CF
3
; —OCF
3
; —CN; amino; nitro; oxime; alkyloxime; or acyloxime;
an aryl group, which aryl group is optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy, alkenoxy, alkynoxy, methylenedioxy, halogen, —OH, —CF
3
, —OCF
3
, —CN, amino, nitro, oxime, alkyloxime, or acyloxime;
a monocyclic 5- to 6-membered heterocyclic group, which heterocyclic group is optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy, alkenoxy, alkynoxy, methylenedioxy, halogen, —OH, —CF
3
, —OCF
3
, —CN, amino, nitro, oxime, alkyloxime, or acyloxime; or
R and/or R
1
, together with the nitrogen atom to which they are attached, represent an alkyl-onium salt, a dialkyl-onium salt, a cycloalkyl-onium salt, an alkyl-cycloalkyl-onium salt, a dicycloalkyl-onium salt, an alkyl-cycloalkylalkyl-onium salt, a cycloalkyl-cycloalkylalkyl-onium salt, or a dicycloalkylalkyl-onium salt.
In another aspect the invention provides pharmaceutical compositions comprising a therapeutically-effective amount of a diazabicycloalkane derivative of the invention, or pharmaceutically-acceptable addition salts thereof, together with at least one pharmaceutically-acceptable carrier or diluent.
In a third aspect the invention relates to the use of the diazabicycloalkane derivatives of the invention for the manufacture of a pharmaceutical composition for the diagnosis, treatment, prevention or alleviation of a disease or a disorder or a condition of a mammal, including a human, which disease, disorder or condition is responsive to the ac
Nielsen Elsebet Ostergaard
Nielsen Simon Feldbaek
Olsen Gunnar M.
Peters Dan
Berch Mark L.
Birch & Stewart Kolasch & Birch, LLP
Habte Kahsay
Neurosearch A/S
LandOfFree
Heteroaryl diazabicycloalkanes, their preparation and use does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Heteroaryl diazabicycloalkanes, their preparation and use, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Heteroaryl diazabicycloalkanes, their preparation and use will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3088278